Appropriate functioning of the immune system is necessary to identify and eliminate pathogens and malfunctioning/cancerous cells. However, recognition of various proteins, small DNA-sequences or other molecules produced by the host body (termed self) as possible pathogenic agents leads to the onset of chronic diseases of the immune system named autoimmune diseases. The immune system is comprised of a variety of T cell subsets, which are responsible for the acquired immune defense. Naïve T cells are those that have never encountered an antigen, while central memory (TCM) and effector memory (TEM) cells were previously exposed to a specific antigen, and provide the memory response. TEM are capable of delivering immediate local tissue responses to antigens on the basis of their reduced activation requirements and increased frequency. In contrast, TCM cells (which constitute ca. 5% of the total memory pool) are capable of rapidly generating a large number of effector cells based on their high proliferative capacity and ability to differentiate into effectors.
The pathology of several autoimmune disorders (such as Multiple Sclerosis (MS), Type 1 Diabetes Mellitus (T1DM), Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE)) has been coupled to the presence of TEM cells which, in the case of MS and RA, have been reported to infiltrate the target tissues and contribute to local tissue damage. For example, in SLE, TEM's are highly expressed and hyperactive, and are thought to contribute to the cardiovascular complications of the disease. Consequently, a therapeutic intervention suppressing the function of TEM may be beneficial in autoimmunity.
The activation and the subsequent effector functions of T cells, such as proliferation and cytokine release, are firmly linked to the sustained elevation of intracellular Ca2+ concentration ([Ca2+]i) triggered by the encounter with an antigen. Ca2+ influx induced by antigen presentation occurs through CRAC (Calcium Release Activated Ca2+) channels that work in concert with other ion channels, transporters and pumps. Particularly, to sustain the driving force for Ca2+ ions through CRAC, two potassium channels, the voltage-gated Kv1.3 and the intracellular Ca2+ activated KCa3.1, maintain the negative transmembrane potential. It was reported that these two K+ channels are differentially expressed in T cell subsets. TEM's from patients with autoimmune diseases (RA, T1DM, MS) are characterized by the high level of Kv1.3 as compared to KCa3.1 channels, hence, the former dominantly regulates the TEM cells' membrane potential. Indeed, Ca2+-dependent activation in these cells can be prevented by application of specific Kv1.3 blockers. The present investigators previously demonstrated that inhibition of Kv1.3 channels with a potent specific inhibitor (ShK from Stichodactyla helianthus, sea anemone) can hamper Ca2+-signaling in SLE T cells.
The treatment of autoimmune diseases requires a very careful strategy, as the systemic application of various drugs can inhibit the function of cells other than the targeted immune cells, which results in ensemble immunosuppression. Several studies reported that blocking of the Kv1.3 channel function by specific peptide toxins and small-molecules in animal models in vivo can be used to inhibit effector functions as well as migration of TEM cells in induced autoimmune deficiencies. However, other cell types express Kv1.3 channels (macrophages, dendritic cell, adipose cells, olfactory neurons), thus raising the possibility of undesirable side effects. Over the past few years more and more papers have been published reporting cell-specific approaches using NPs that had demonstrated fewer or no side-effects as compared to the systemic application of drugs generally.
An exemplary autoimmune disorder is Systemic Lupus Erythematosus (SLE). Currently approved therapies have serious side effects and, in many cases, limited efficacy. Emerging new therapies still undergoing clinical trials focus on the regulation of T and B cell function (Paz, Z., and G. C. Tsokos. 2013, Curr Opin Rheumatol 25:297-303, the disclosure of which is incorporated herein by this reference). These cells, in fact, play an important role in the pathogenesis of SLE. In particular, autoantigen-specific memory T (TM) cells infiltrate the tissues, secrete inflammatory cytokines and reactivate accumulating B cells through cytokine production and direct CD40L-CD40 binding.
The CD40-CD40L interaction plays a particularly important role in SLE patients because CD40L is overexpressed in these patients' T cells. CD40L is a member of the tumor necrosis factor (TNF) superfamily located on activated T cells, and binds its receptor, CD40, on the B cells. This interaction stimulates B cell activation which, in turn, leads to inflammatory cytokine release, autoantibody formation and end-stage organ damage. Importantly, TM cells guarantee life-long persistence of immune memory and long-lived active B cells. Therefore, it is widely accepted that lupus cannot be cured without disarming these cells. Therapeutic interventions aiming to interrupt the reciprocal interaction between B and T cells via the CD40-CD40L pathway have shown some efficacy in SLE patients; however an increased risk of thrombotic complications have unfortunately halted clinical trials (CD40L is expressed in platelets). Clearly, new ways of selectively targeting TM cells to disrupt the T-B communication pathways involved in lupus and other autoimmune disorders having similar etiological considerations are needed.